Stabilized solutions of local anesthetics



Patented Nov. 25 1947 STABILIZED SOLUTIONS OF LOCAL ANESTHETICS William F. Hamilton, Altadena, Califi, assignor to Frederick M. Turnbull, Los Angeles, Calif.

Application'July 24, 1945, Serial No. 606,804

2 Claims.

This invention relatesto the stabilization of aqueous solutions of B-diethylaminoethyl p-ethoxybenzoate hydrochloride which are useful local anesthetics. In aqueous solution, this anesthetic slowly hydrolyzes to form p-ethoxybenzoic acid which is relatively insoluble. Precipitation of this acid occurs, rendering the pharmaceutical unfit for therapeutic uses, especially injection.

This invention is directed to the stabilization of an aqueous solution of fiediethylaminoethyl p-ethoxybenzoate hydrochloride against those factors tendingto cause the formation of a precipitate therein uponprolonged standing which renders the solution unfit for use.' ,B-diethylaminoethyl p-ethoxybenzoate hydrochloride is known and commercially sold under the trade names Diethoxin and Intracaine.

,B-Diethylaminoethyl p-ethoxybenzoate hydrochloride is a local anesthetic possessing great efficacy and other desirable properties rendering desirable its more extended use. For example, in man and in other animals it is efiective in about have the strength of novocaine or of procaine (p-diethylaminoethyl p-aminobenzoate hydrochloride) and produces an infiltration or nerve block anesthesia which lasts appreciably longer than that produced by an equivalent amount of such novocaine or procaine. [,B-diethylaminoethyl p-ethoxybenzoate hydrochloride is more immediate and uniform in its action than novocaine and in most instances is as effective without the addition'of epinephrine, as is novocaine with epinephrine, probably because of its longer duration of activity and because of its greater tendency to spread beyond the immediate zone of infiltration.

The use of this local'anesthetic has been restricted by the fact that in a comparatively short time after an aqueous solution is formed of a concentration desirable for intravenous injection, e. g., up to 2%, a precipitate may be formed after sterilizing, rendering the solution unfit for such use. For example, if an'aqueous solution of 1 or 2% of p-diethylaminoethyl p-ethoxybenzoate hydrochloride is refluxed continuously, in a short time, i. e., one hour, such a precipitate is formed after cooling, While only a small proportion, probably in the neighborhood of about 5%, of the total fl-diethylaminoethyl p-ethoxybenzoate hydrochloride present; in the aqueous solution precipitates after extended storage, the precipitate is sufilcient to render the solution useless for injection.

The precipitate formed by hydrolysis of the ,s-diethylaminoethyl p-ethoxybenzoate hydrochloride: 1

(n) C2115 C-O-CHz-CHz-N -HC1 CHzCHz It has long been recognized that, if an aqueous solution of ,B-diethylaminoethyl p-ethoxybenzoate hydrochloride could be stabilized so that no precipitate was formed therein over those periods of time necessary to permit of its manufacture, distribution through the ordinary trade channels, and storage for reasonable periods by physicians and other users, the extent of use of this local anesthetic would be greatly enhanced. The period of time necessary to permit of such manufacture and distribution of such a solution varies, of course, with the character of the intended use of the solution, being less, for example, when the solution is distributed to hospitals directly for their use than when it is distributed to pharmacies for use by physician customers. The period of stability required for such a solution may be defined as that which is substantially greater than the maximum time that an aqueous solution of fl-diethylaminoethyl p-ethoxybenzoate hydrochloride may be storedwithout precipitation and as including such greater periods of time, amounting even to years, e. g., two or three years, necessary for its distribution through those commercial channels in which it is stored for the greatest periods, and it is such stabilization that is meant when there is employed herein the term stabilized solution or the stabilizing agent is referred to as "providing stability.

Although such recognition and the demand for such a stabilized solutionhas long existed and it has been quite apparent to those skilled in the art that the provision of such a stabilized solution would provide substantial profit to its originator, no one, to the best of my knowledge and I reacts with the p-ethoxybenzoic acid, having the formula:

OCHzOHs to form the product p-ethoxybenhoyl salicylic acid, having the formula:

I have discovered that salicylic acid will not cause the p-ethoxybenzoic acid, after it has precipitated, to redissolve in an aqueous solution of ,B-diethylaminoethyl p-ethoxybenzoate hydrochloride. I have discovered that the same qu'antity of salicylic acid'added to anaqueous 'solution of p-diethylaminoethyl p-ethoxybenzoate I hydrochloride of the same concentration, prior tothe precipitation of any p-ethoxybenzoic acid, will prevent the precipitation of p-ethoxybenzoic acid; for example, when an aqueous solution of ,c-diethylaminoethyl ,p-ethoxybenzoate hydrochloride in concentration of 1%. is. refluxed for one hour and cooled, p-ethoxybenzoi'c. acid precipitatesh, While this precipitate is redissolved when the solution is reheated, it isiagair'ipre-v cipitated when the solution. iscooled. .When 7 there is added tothis solution salicylic. .acid in. concentration of .005 the precipitate is dis-3,55 solved upon heating the solution, butagain' precipitates whenthe solution is, cooled.

Whensalicylic acid in concentration of .005% is added initially to an aqueous solution ofp-diethylaminoethyl p-ethoxybenzoate hydrochloride. in concentration of 1% and the. solution is. refluxed for one hour, no precipitate is formed on. cooling, and the solution remains stable for extended periods of time.

While I do notwish to be bound by this the- 6 cry, I believe that the explanation of this phe-. nomenon is that the p-ethoxybenzoic acid in. its nascent state may react withthesalicylic acid to form a somewhat water-soluble reaction product; p-ethoxybenzoyl salicylate, andthat the p -ethoxybenzoic acid, after passing through its nascent state, is less reactive to such an extent that it. reacts not 'at all or not to an appreciable extent with thesalicylic acid. e 1m Thus, in "accordance with the invention, I have 76 secured varyingziiegrees of stability of a 1% solution of qS-diethylaminoethyl p-ethoxybenzoate hydrochloride with varying concentrations of salicylic acid. A 0.1% concentration of salicylic acid in such a solution of fl-diethylaminoethyl p-ethoxybenzoate hydrochloride stabilized the 11319 5 1 W 11% sma e e s in a stopperd flas k;in;a,wate h ataternperature of 105 F. 'for three months, there was formed only a very slight amount of precipitate after cooling. Employing concentrations of 0.06%, 0.05%, and 0.035% of salicylic acid in a 2% solution of p-diethylaminoethyl p-ethoxybenzoate hydrochloride, it wasiound that, when the solutionsweresubjected to identical conditions for three months, the quantity of precipitate formed after-,coolingdecreased with decreasing concentration oi salicylic acid.

It is believed that the optimum concentration of the salicylic acid for stabilizing a 1 solution of I fi-diethyla minoetli yh p-ethoxybenzoate hydro chloride is 0.0229 gram per i m of-drug in solution This belief -is-based-upon the assumption that .equimolalproportions"are required. Ifit be assumed that 5% of fi diethylaminoethyl.p ethoxybenzoate' hydrochloride in a 1% aqueoussolution of cc, hydrolyzes, there is I provided or 0-.0 2;"75 g If the salt isformedzbya 1:1 reaction, then the number of grams-of-salieylic acidlper 100 cc. of

r such 1% solution required fortthe reaction is oat-siege:

or a Confirm n -1 a tion or fx -diethy am noe ylp fluxingf when only 31% o hqtrb nto'at hvd o ho legilf ebwtiqum riod" of time necessary It ma sfidfiheifiere that e e eoussm lution a 1% f. flrd ethrlaminq thyli p I. ethoxyben'z'oate'hydrochloride is eifectively stabilizedin the commercial sense" that the word is employed herein with concentrations of salicylic acid of less -'tha1 i -'.-03 thelconcen tration of salij cylicacid varyirigWi-th'th degree or extent of stabilizationacquired. l

For-.each. concentration of fl -diethylaminoethyl p-ethoxybenzoate hydrochloride -in-aqueous solution, there appears to be a definite optimum in the amount of salicylic acid which should be-add ed to give. maximum'stability;- for example, about 025% salicylic acid contained in a aqueous e pn, 5 .1%v 0 k t s rb n ate hy-.. oc eliide-w t u any el qxlis afi ddigrms. precipitate oncoplingafterlonlyone hpur of re-,

h lefi i ie thyl p-i r. nt i nitai .isrmed on fl lin iu til .re ux erhes been 9 1:.

, tan-1 ac aithe. solution I is,

, ur oiqei n u flu al uxine rm: l hl? hq i s eqn ilt t sayery. ri or ous't'est, undoubtedly more severe than required for 9mm il 1 efi bllii ...t St bi t n precipitation in a seale d container ior that peg, ne miti i s men f c ture by a 'p h'armaceu al house, its, distribution through t r, q eniiels of t a e o the' solution gives greater stability than does either increasing or decreasing amounts of salicylic acid. Similarly, for a 1% solution of p-diethylaminoethyl p-ethoxybenzoate hydrochloride, the optimum is somewhat higher and lies between about .03 and about .1% salicylic acid added. Likewise, for the 2% concentration of 5-diethylaminoethyl p-ethoxybenzoate hydrochloride, the optimum apparently lies between about .02 and about 04% salicylic acid in the B-diethylaminoethyl pethoxybenzoate hydrochloride.

This is probably due to the fact that the prodduct formed by hydrolysis of 8-diethylaminoethyl p-ethoxybenzoate hydrochloride and deposited as a precipitate indicative of the stability of the solution has a limited solubility, so that only enough salicylic acid need be added to the solution to reduce the quantity of such product formed or remaining in the solution to below its saturation point in the solution. Contributing to this phenomenon also is'probably a variation in the solubility or saturation point of the product comprising the precipitate caused by the increased concentration in the solution of B-diethylaminoethyl p-ethoxybenzoate hydrochloride.

It is desirable also to employ in the solution no more than that quantity of salicylic acid necessary to provide the required stability, because, in accordance with this invention, it is desired to avoid the possibility of increased salicylate toxicity which such an excess of salicylic acid might induce.

Presented in the drawing are three curves, A, B, and C, representing concentrationsof p-diethylaminoethyl p-ethoxybenzoate hydrochloride in aqueous solutions of 0.5, 1, and 2%, respectively. In each of these curves there is plotted the concentration of salicylic acid added to such aqueous solution, as the abscissa, against stability of the solution as measured in reflux time in hours required to produce noticeable precipitation after cooling, as the ordinate. As clearly appears from curve A, the optimum percentage of salicylic acid for providing stability to an aqueous solution of 0.5% of ,B-diethylaminoethyl p-ethoxybenzoate hydrochloride is about 0.025%. As clearly appears from curve B, the effect of increasing increments of the concentration of the salicylic acid in an aqueous solution of 1% B-diethylaminoethyl p-ethoxybenzoate hydrochloride diminishes above about 010%. As appears from curve C, the efiect of an increase in the increments of percentage of salicylic acid added to an aqueous solution of 2% p-diethylaminoethyl p-ethoxybenzoate hydrochloride diminishes above about .010%.

For all such solutions, including those up to about 2% B-diethylaminoethyl p-ethoxybenzoate hydrochloride, a concentration of salicylic acid of .0125 gram per gram of fi-diethylaminoethyl pethoxybenzoate hydrochloride in aqueous solution provides stability in about five hours or more of refluxing without the formation of a precipitate upon cooling of the solution. It may be said that each hour of such refluxing followed by cooling is the equivalent of about three months storage in a stoppered container at room temperature of about 20 C. in its effect upon the formation of a precipitate in the solution.

Hence the stability provided by such a concentration of .0125 gram of salicylic acid per gram of p-diethylaminoethyl p-ethoxybenzoate hydrochloride in aqueous solution will stabilize the solution for a period of the order of years, as contrasted with the stability of an aqueous solution of ,B-diethylaminoethyl p-ethoxybenzoate hydro- 6 chloride of the order of months in the absence of salicyclic acid, and such a concentration of salicyclic acid as a stabilizing agent in an aqueous solution of ,B-diethylaminoethyl p-ethoxybenzoate hydrochlorideis embraced within the term stabilized solution and the term providing stability, as employed herein.

It will bev obvious to anyone skilled in the art from the data herein presented and from the curves in the drawing that the concentration of salicyclic acid addedto an aqueous solution of a given concentration of B-diethylaminoethyl pethoxybenzoate hydrochloride may be varied as determined by the degree of stability required for the intended use of the solution. The concentration of salicyclic acid for the stability required for various uses falls between approximately 0.5 and 2.5% of the p-diethylaminoethyl p-ethoxybenzoate hydrochloride present in the solution.

There may be added to the stabilized solutions of fl-diethylaminoethyl p-ethoxybenzoate hydrochloride previously described a suitable vasoconstrictor, such as desoxyephedrine hydrochloride,

neosynephrine hydrochloride, amphetamine sulfate or hydrochloride, or epinephrine hydrochloride in concentration to provide the desired restriction to local absorption of the B-diethylaminoethyl p-ethoxybenzoate hydrochloride and the avoidance of its systemic absorption.

By way of example, about .02% of desoxyephedrine in an aqueous solution of about 1% ,B-diethylaminoethyl p-ethoxybenzoate hydrochloride with salicylic acid in concentration of about .0125% to provide the desired stability has been found suitable for this purpose. Likewise a concentration of epinephrine in the solution in the proportions of about 1:50,000 is suitable for this purpose.

Unexpected results'are secured utilizing a stabilized aqueous solution of B-diethylaminoethyl pethoxybenzoate hydrochloride with a suitable vasoconstrictor therein when applied to the surface of mucous membrane or other tissue, in that both the anesthetic effect of the B-diethylaminoethyl p-ethoxybenzoate hydrochloride and the constricting efiect of the vasoconstrictor are enormously enhanced. p-diethylaminoethyl pethoxybenzoate hydrochloride, when applied alone to the surface of mucous membrane or other tissue, has very little anesthetic effect, and it is for that reason that its use has heretofore been substantially confined to hypodermic injection where its anesthetic effect is secured by infiltration. Vasoconstrictors, when applied to such surfaces, have no substantial constricting effect in minute concentrations; for example, the constricting effect of desoxyephedrine hydrochloride is not secured to a desired extent in concentrations of this vasoconstrictor alone in aqueous solution of less than about 1%.

In spite of these facts, utilizing a solution of .02% of desoxyephedrine hydrochloride in an aqueous solution of about 1% p-diethylaminoethyl p-ethoxybenzoate hydrochloride stabilized with salicyclic acid in concentration of about .0125%, it has been found that both very substantial vasoconstrictive and anesthetic effects are secured upon surface application to mucous membrane and other tissue. While I do not wish to be restricted to any explanation of this surprising result, the evidence makes it appear extremely probable either that synergism or compound formation occurs between the vasoconstrictor and p-diethylaminoethyl p-ethoxybenzoate hydrochloride, the hydrolysis products of 7 pedi'ethylaminoethyl -"thoxyben'zeate hydro; ch1oride,'= or the 's alicyclic acid; 01 alt er-some of Because of suchefiects, it is desirable in some instances tc addto an aqueous solutionyof 'novo cameacvasoconstrictor with" saueygnc acid in" concentrations of the order-ofthose-hereiribefore setforth-, in-' order to enhance the anesthetic effect of the p-diethylaminoethyl -p-aminobenzoet hydrochloride and the constricting effect of the vasoconstr-ic'tor while utilizing reduced concentranoneream,-

Fr-om the-foregcing specific examples givenonly by way of illustration of-the invention; it willbe se'en thatfor any given concentration of the 8- diethylaminoethyl p-ethox'ybenzoate v-hydrochlo ride in aqueous solution up to-the limitpf its usef-ulness there-is employed-as a stabiliz'inga 'r it that concentration ofsalicyclic acid which is" com pattib1e --withthe solution in the sense tha t it" is greai'tw enough to enhance substantially the period of "time" within which no precipitation occurs in the 1 solution over that period of time in. which such precipitation would occur inthe absence-of the salicyclicacid and in the sense that "the-co n i tiv q my nv t q rmyinve derstdodas not restricted to such P a p -ethoziylcencate 'hy' F; HAMILTON.

REFERENCES CITED renewing references are of record in the file of this, p'aLtent: v

1 UNITED sT'ATEs PATENTS @530'795 Seyde l Nov. 6, 1928 Goldberg" Aug. 29,1933 7, s FOREIGN PATENTS v OTHER REFERENCES Gutfixad Modern Drug Encyclopedia), 2:: ed. (1 94 1),- pa;ge 305. (Copy in' ivision 43 Certificate of Correction Patent N 0. 2,431,553. November 25, 1947. WILLIAM F. HAMILTON It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Column 6, lines 2, 2 and 3, 11, 16 and 65; column 7, lines 2, 6, 19, 25, 28, 31 and 32; column 8, lines 9 and 10, 12 and 13, for the word salicyclic read salicylic; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Ofiice.

Signed and sealed this 2nd day of March, A. D. 1948.

THOMAS F. MURPHY,

Assistant Oommz'ssioner of Patents. 

